Two phase compositions for absorbable surgical devices

ABSTRACT

An absorbable, annealed surgical device made from a multi-phase, polymeric composition derived from lactide and glycolide. Preferably, the composition has two phases, both phases are continuous, the first phase has about 0-about 25%m glycolide moieties, the overall composition has up to 45%m glycolide moieties, and the first phase constitutes at least 50% (and preferably not more than about 95%) by weight of the composition. The device has a high distortion temperature, good resistance to hot-wet creep, but yet loses tensile strength in vivo quickly. The composition per se is injection-moldable, can be annealed, and is not brittle.

This is a continuation of Ser. No. 07/117,466, filed Nov. 5, 1987 (nowabandoned) which is a division of Ser. No. 07/099,635, filed Sep. 22,1987 (now abandoned) which is a continuation of Ser. No. 06/860,302,filed July 17, 1986 (now abandoned) which is a continuation of Ser. No.06/586,686, filed Mar. 6, 1984 (now abandoned).

BACKGROUND OF THE INVENTION

Polymers and copolymers of, and surgical devices made from, lactideand/or glycolide and/or related compounds are well-known. See, e.g.,U.S. Pat. Nos. 2,668,162, 2,683,136, 2,703,316, 2,758,987, 3,225,766,3,268,486, 3,268,487, 3,297,033, 3,422,181, 3,442,871, 3,463,158,3,468,853, 3,531,561, 3,565,869, 3,597,449, 3,620,218, 3,626,9478,3,636,956, 3,736,646, 3,739,773, 3,772,420, 3,773,919, 3,781,349,3,784,585, 3,792,010, 3,797,499, 3,83,297, 3,846,382, 3,867,190,3,875,937, 3,878,284, 3,896,802, 3,902,497, 3,937,223, 3,982,543,4,033,938, 4,045,418, 4,057,537, 4,060,089, 4,137,921, 4,157,437,4,243,775, 4,246,904, 4,273,920, 4,275,813, 4,279,249, and 4,300,565,U.K. Pat. or Appln. Nos. 779,291, 1,332,505, 1,414,600, and 2,102,827,D. K. Gilding et al., "Biodegradable polymers for use insurgery--polyglycolic/poly (lactic acid) homo-and copolymers: 1,"Polymer, Volume 20, pages 1459-1464 (1979), and D. F. Williams (ed.),Biocompatibility of Clinical Implant Materials, Volume II, chapter 9:"Biodegradable Polymers" (1981). Multi-phase polymeric compositions areshown in Matsuo et al., "Fine Structures of Styrene-Butadiene BlockCopolymer Films Cast from Toluene Solution," Polymer, Volume 10, pages79-87 (1969). All of the foregoing documents are hereby incorporated byreference.

Some of those documents mention or discuss makinglactide/glycolide/related compound polymers or copolymers of smallparticle size. See, e.g., U.S. Pat. Nos. 3,781,349 and 3,846,382.

Some of those documents mention or discuss multi-stage or sequentialaddition of monomers in making the lactide/glycolide/related compoundpolymers or copolymers. See, e.g., U.S. Pat. Nos. 3,268,486, 3,268,487,3,784,585, 4,137,921, 4,157,437, 4,242,775, and 4,300,565.

Some of the documents first listed mention or discuss multi-phase orblock systems containing the lactide/glycolide/related compound polymersor copolymers. See, e.g., U.S. Pat. Nos. 3,268,486, 3,268,487,3,463,158, 3,773,919, 3,784,585, 3,875,99 4,045,418, 4,057,537,4,137,921, 4,157,437, 4,243,775, 4,279,249, and 4,300,565, U.K. Pat. No.1,332,505, Gilding et al., and Williams.

Some of the documents first listed mention or discuss annealing,heat-treating, or post-treating surgical articles containing thelactide/glycolide/related compound polymers or copolyemers. See, e.g.,U.S. Pat. Nos. 3,422,181, 3,626,948, 3,636,956, 3,772,420, 3,792,010,3,797,499, 3,839,297, 3,878,284, 4,137,921, 4,157,437, 4,243,775, and4,300,565, and U.K. Pat. or Appln, Nos. 1,332,505, 1,414,600, and2,102,827.

In particular, some of the documents first listed mention or discussannealing, heat-treating, or post-treating surgical articles made ofpoly(lactide/glycolide) copolymers made by multi-stage or sequentialaddition of the monomers. See, e.g., U.S. Pat. Nos. 4,137,921,4,157,3437, 4,243,775, and 4,300,565. In those documents, glycolidemoieties constitute more than 50% by weight of the lactide/glycolidecopolymers.

It is known that annealing polymers, copolymers, and surgical devicesmade from lactide and/or glycolide and/or related compounds increasesthe crystallinity and in vivo tensile strength retention of thepolymers, copolymers, and surgical devices. It is also known that thegreater the crystallinity, the longer such polymers, copolymers, andsurgical devices retain their in vivo tensile strength. See some of thedocuments first listed, e.g., U.S. Pat. Nos. 3,636,956 (particularlycolumn 2, line 43 et seq.), 4,137,921 (particularly column 9, lines61-64), U.K. Appln. No. 2,102,827, and Williams (particularly pages222-224). It is also known that increasing the crystallinity of suchpolymers and copolymers makes them more brittle and, thus, decreasestheir utility as injection molded surgical devices.

SUMMARY OF THE INVENTION

It has now been found that certain two-phase compositions derived fromlactide and glycolide in which lactide moieties predominate have aremarkable and unexpected balance of desirable properties. Thoseproperties include lack of brittleness and the ability to be injectionmolded and annealed. The properties of the composition, in turn, make itpossible to injection mold surgical device (e.g., staples, clips) fromthe composition and to anneal those devices to obtain devices having aremarkable and unexpected balance of desirable properties.

A problem with substantially amorphous one-phase poly(lactide/glycolide)devices wherein lactide moieties predominate is their occasionally lowdistortion temperature. (Substantially amorphous one-phasepoly(lactide/glycolide) devices and compositions therefore are disclosedin commonly-assigned U.S. Pat. application Ser. No. 436,056, filed Oct.22, 1982, which is hereby incorporated by reference.) Thus, even thetemperature on an extremely hot summer day in Ariz., for example, may besufficient to cause such devices to deform slightly. Annealing suchdevices often deforms them so significantly (even if held in a moldduring annealing) that they are no longer useful as surgical devices.

Surprisingly, as compared to a substantially amorphous, one-phasepoly(lactide/glycolide) device of a given composition, the new annealed,two-phase device of the same overall composition has a much higherdistortion temperature but essentially the same in vivo rate of loss oftensile strength. Thus, the present compensation makes it possible toincrease the resistance to thermal distortion of poly(lactide/glycolide)surgical devices without adversely affecting their rate of loss oftensile strength. The new devices also have surprising resistance tohot-wet creep. Also surprising and contrary to the suggestions of theart is that the step of annealing the new two-phase compositionincreases its crystallinity and tensile strength but decreases (notincreases) the time required for it to lose tensile strength in vivo.Other advantages of this invention will be apparent to one skilled inthe art.

In one aspect, the present invention relates to an absorbable, annealedsurgical device of a multi-phase polymeric composition derived fromlactide and glycolide, the first phase having about 0-about 25% mglycolide moieties and about 75-about 100% m lactide moieties and theother phases having glycolide and lactide moieties in amounts such thatthe composition overall has up to 45% m glycolide moieties, wherein thefirst phase constitutes at least 50% (and preferably not more than about95%) by weight of the annealed surgical device. As the glycolide moietycontent of the first phase approaches zero, the composition tends tobecome brittle. At some point the material will be too brittle forforming useful surgical devices. The exact lower limit of usefulglycolide moiety content is not known.

In another aspect, the present invention relates a process for making asurgical device comprising the steps:

(a) polymerizing a first monomer mixture containing a predominant amountof lactide until the polymerization is substantially complete, therebyforming a first polymer;

(b) adding to the first polymer (with or without prior recovery andpurification of the polymer) a second monomer mixture containingglycolide and polymerizing the second monomer mixture in the presence ofthe first polymer, thereby forming a second polymer having two phases:

(c) recovering the final polymer from the final polymerization stage(with or without purification of the polymer);

(d) forming a surgical device from the final polymer; and

(e) annealing the surgical device;

(f) the quantities of monomers being chosen so that (i) the first phaseof the final polymer has from about 0-about 25% m glycolide moieties andabout 75-about 100% m lactide moieties, (ii) the final polymer overallhas up to 45% m glycolide moieties, and (iii) the first phaseconstitutes at least 50% (and preferably not more than about 95%) byweight of the surgical device.

In another aspect, the present invention relates to a process for makingsurgical device comprising the steps:

(a) preparing a first polymer containing about 0-about 25% m glycolidemoieties and about 75-about 100% m lactide moieties;

(b) intimately mixing with the first polymer, particles of a secondpolymer containing a predominant amount of glycolide moieties, therebyforming a two-phase polymeric composition wherein the first phaseconstitutes at least 50% (and preferably not more than about 95%) byweight of the two-phase composition;

(c) forming the surgical device from the two-phase polymericcomposition; and

(d) annealing the surgical device.

In another aspect, the present invention relates to an annealable,infection-moldable lactide/glycolide polymeric composition having atleast two phases wherein the first phase contains about 0-about 25% mglycolide moieties in amounts such that the overall composition containsup to 45% m glycolide moieties and wherein the first phase constitutesat least 50% (and preferably not more than bout 95%) by weight of thepolymeric composition.

As used herein, "% m" means mole percent and "moiety" means that portionof a polymer derived from a particular monomer. Thus, a "glycolidemoiety" of a polymer is a portion of the polymer derived from a startingglycolide monomer. As used herein, "substantially amorphous" meanshaving 10% or less crystallinity (see, e.g., U.S. Pat. No. 3,878,284,column 3, lines 16-18). "Distortion temperature" means the temperatureat which the dimensions of a surgical device start to changesignificantly because of flow of the material of the surgical device.

DETAILED DESCRIPTION OF THE INVENTION

The glycolide and lactide employed in making the new two-phasecomposition can be obtained commercially or may be made using knowntechniques. A preferred way of making the glycolide is as follows.Hydroxyacetic acid (glycolic acid) is heated under nitrogen to 180° C.to remove water. Pressure is then reduced and heating is continued fortwo hours to yield a prepolymer of polyglycolic acid, which is recoveredand powdered.

The prepolymer is heated in the presence of Sb₂ O₃ at 275° C. under lowpressure with an argon purge and stirring. The prepolymer cracks andglycolide is distilled over and recovered in a cold vacuum receiver. Anypurification technique that yields pure enough monomers may be used.Preferably, the glycolide is purified by conventional techniques, suchas distillation, crystallization, and sublimation.

L-lactide is used along or in combination with a small amount of the DLracemer. The amount of DL racemer, if used, should be low enough so thatcrystallization of the lactide-rich phase is not inhibited. L-lactide ispurified by crystallization from toluene solution. The DL racemer, ifused, is purified by crystallization from ethyl acetate.

The preferred two-phase polymeric lactide/glycolide composition of thisinvention has a lactide-rich phase having about 0-about 25% m glycolidemoieties and a glycolide-rich phase containing lactide and glycolide inamounts such that the composition overall contains up to 45% m glycolidemoieties wherein the lactide-rich phase constitutes at least 50% byweight of the two-phase composition. Preferably, the lactide-rich phasehas 10-20% m glycolide moieties and the composition overall has 30-45% mglycolide moieties. Most preferably, the lactide-rich phase has about10% m glycolide moieties and the composition overall has about 35% mglycolide moieties.

The two-phase compositions of this invention will either comprise acontinuous lactide-rich phase interpolymerized with a continuousglycolide-rich phase or will comprise a continuous lactide-rich phasehaving dispersed throughout it discrete particles of a glycolide-richphase. The former (continuous/continuous) is preferred and may bethought of as a limiting case of the latter (continuous/discrete),wherein the glycolide-rich particles are close enough to each other tobe a continuous phase. In the continuous/discrete case, the lactide-richphase is the matrix or continuous phase and the glycolide-rich dispersedparticles together constitute the dispersed phase. In both cases,particles of a polymer containing glycolide moieties in a separate phaseare distributed throughout a lactide-rich continuous phase."Lactide-rich" phase and "glycolide-rich" phase mean containing apredominant amount of lactide moieties and containing a predominantamount of glycolide moieties, respectively.

The interpolymer two-phase polymeric compositions of this invention(continuous/continuous) may be made by polymerizing in a first stage afirst monomer mixture, adding to the resulting polymer a second monomermixture, and then in a second stage polymerizing the second monomermixture while in intimate contact with the polymer of the first stage.Electron scanning mimeographs of these compositions show that each phaseis continuous, that is, the minor, glycolide-rich phase is continuouslyinterpolymerized within the major lactide-rich phase. Any suitablepolymerization technique may be used. See, for example, those disclosedin the documents listed in the Background Of The Invention, above. Thereare two general polymerization schemes for making the interpolymercompositions of this invention.

First, the polymer resulting from the first-stage polymerization may berecovered, purified, and stored (if necessary) before adding the secondmonomer mixture to it and carrying out the second-stage polymerization.Alternatively, the first-stage polymerization may be carried out in areactor and then, without recovering or purifying the resulting polymer,the second monomer mixture may be added to the same reactor and thesecond-stage polymerization carried out. The second scheme has fewersteps than the fist scheme (because of the elimination of recovery,purification, and possible intermediate storage), but the first schemeallows for better quality control of the characteristics of theintermediate polymeric product. Which scheme is used will depend upon avariety of factors, including cost and the need to control thecharacteristics of the intermediate polymeric product.

Recovery and purification of the intermediate polymer from the firstreaction stage (if desired) and recovery and purification of the finalpolymer from the second reaction stage are accomplished in the followingmanner. The reaction product is isolated (e.g., removed from thereactor), comminuted, and treated to remove residual reactants. Polymerparticle size is usually a few millimeters. Particles too small areundesirable. A sufficient amount of unreacted monomer is removed so thatthe annealed surgical device and the annealable polymeric compositionhave the desired properties (e.g., high enough distortion temperatureand a high enough molecular weight).

Any method capable of removing the unreacted monomers may be used,provided that method results in the polymeric product having the desiredproperties and does not adversely affect any other important propertiesof the final polymer. The preferred purification procedure is asfollows.

After communition, the crude reaction product is contacted with ethylether for about 72 hours in a Soxhlet-type extractor to remove unreactedmonomer. Typically, in each stage 4-10% of the starting monomers remainunreacted.

After the extraction period, the partially purified polymer is slowlyheated under vacuum from ambient temperature to 130° C. over a period ofabout 100 hours. The slow rate of heating is important to preventmelting (strictly speaking, flowing together) of the copolymer particlesand to remove any water present. Dry inert gas may be used to purge thesystem, and occasionally the heating step may require more than 100hours for the polymer to reach the desired properties. This procedureremoves any residual solvent (ethyl ether) present.

After removal of unreacted monomers (and of solvent, if solventextraction is used), the purified copolymer must be dried if it was notdried enough in the monomer removal step and, in any event, stored tokeep it dry. The intermediate and final polymers must be as dry aspossible before forming surgical devices from the final compositionbecause the presence of too much water in the polymers results ininherent viscosity (molecular weight) dropping below the minimumacceptable levels during forming the surgical device. Generally, it isdesired that the polymers be dried to a dry state and stored at arelative humidity of no more than a few percent. Preferably, thepurified dried polymers (intermediate, if any, and final) are storedunder a vacuum and/or with a dry inert gas pad. As will be understood byone skilled in the art, the length of storage affects the allowablerelative humidity for storage, higher humidity levels being moreacceptable if storage is to be for a shorter period of time.

The two-phase composition of this invention having a continuouslactide-rich phase and a discrete particle glycolide-rich phase may bemade by forming the polymers of the two phases separately and thenmixing small particles of the glycolide-rich polymer into thelactide-rich polymer. Mixing may be accomplished in conventionalequipment (provided the polymeric materials are kept dry enough), forexample, in the surgical device-forming equipment.

Each polymer may be made separately in the manner described above andthen the glycolide-rich polymer comminuted to a fine particle size(generally 10 microns or less) before mixing. Smaller particles givebetter results. A long grinding period is usually disadvantageousbecause during grinding, the glycolide-rich polymer may pick up too muchmoisture from the ambient atmosphere (even if grinding is performed in adry room), and that will adversely affect the properties of the finaldevice. Accordingly, it is preferred that the glycolide-rich phase bepolymerized using a technique that results in the particles being smallenough so that a comminuting step is relatively short or not needed atall.

Whichever two-phase composition is used (continuous/continuous orcontinuous/discrete), the absorbable devices are made preferably byinjection molding the final, purified, two-phase polymeric compositionusing, for example, a screw injection molding machine. The resultingdevices have a first phase containing about 0-about 25% m glycolidemoieties and an overall composition of up to 45% m glycolide moietiesand the first phase constitutes at least 50% (and preferably not morethan about 95%) by weight of the devices.

A preheated vacuum hopper retrofitted to the screw injection moldingmachine has been found to be useful for maintaining the purified driedcopolymer in a dry condition. The vacuum hopper comprises a vesselupstream of the machine's standard hopper. The vessel must be capable ofoperating under vacuum and of being heated.

The preferred procedure for injection molding the devices is to placethe purified dried copolymer particles in the vacuum hopper under avacuum, heat the hopper to 50°-70° C., and hold temperature and vacuumfor at least an hour, preferably about 15 hours. The pressure in thevacuum hopper is desirably no higher than 5 mm Hg and preferably nohigher than 0.1 mm Hg. The standard hopper must also be heated and driedbefore allowing the purified, dried two-phase polymeric composition topass from the vacuum hopper into the standard hopper. The entireinjection molding system desirably is padded and/or purged with a dryinert gas. Injection molding is generally carried out at a temperaturebelow the melting point of the glycolide-rich phase.

The design of the surgical devices is not critical insofar as thepresent invention is concerned. The devices may, for instance, bestaples or clips. Examples of staples and clips which can be made fromthe polymers of this invention are shown in U.s. Pat. Nos. 4,060,089 and4,402,445 and in U.S. Pat. application Ser. Nos. 429,249 and 429,250,both filed on Sep. 30, 1982, all of which patents and applications arehereby incorporated by reference. Other possible device designs will beknown to those skilled in the art.

The formed devices are then annealed (or heat-treated), preferably whileheld in restraining fixtures, e.g., molds. Holding them in restrainingfixtures prevents the annealing step from deforming the devices. Thedevices are held at 80° to 130 ° C. for from 10 to 120 minutes, shortertimes being used with higher temperatures. The temperature may be heldconstant at a single value or held constant at two or more values instages. For a preferred polymeric composition having about 10% mglycolide moieties in the lactide-rich phase and about 35% m glycolidemoieties overall, the devices are annealed preferably by keeping them atabout 90° C. for about 90 minutes.

Infection molding reduces the crystallinity of the lactide-rich phasefrom 5-10% to about zero but usually has no effect on the crystallinityof the glycolide-rich phase, which is about 1-5%. Annealing impartscrystallinity to the lactide-rich phase (raising it to about 10-20%) buthas little effect on the glycolide-rich phase (crystallinity rises, ifat all, to a maximum of about 10%). These crystallinities are calculatedbased on the entire composition using x-ray diffraction.

A preferred procedure for making the two-continuous-phase compositionaccording to the first scheme (recovery and purification of theintermediate polymer product) is as follows. This discussion describesmanufacture of a particular composition having about 10% m glycolide inthe lactide-rich phase and about 30% m glycolide moieties overall. Thequantities of reactants given may be varied depending on the particularcomposition desired.

Lactide (5,620 grams) and glycolide (503 grams) are charged to a reactorunder an argon blanket. A solution of stannous octoate catalyst indiethyl ether is added to give 0.02% w of catalyst, based on the totalweight of lactide and glycolide. Sufficient initiator (pure glycolicacid) is added to control the molecular weight so the desired inherentviscosity is achieved. The reactor is further purged with argon and heldat 5 psi while heating to 170°-175° C. Pressure and temperature aremaintained for six hours. The reaction product is then recovered andpurified in the manner described above.

The intermediate polymeric product is carefully dried in a vacuum oven(≦1 mm Hg) by heating at 70° C. for 6 hours and then 100° C. for 6hours. The polymer is allowed to cool to ambient temperature in thevacuum oven. The initial inherent viscosity of the copolymer should beat least 1.9, preferably 2.2. Lower inherent viscosities (e.g., 1.3) maybe used if the polymeric product is kept very dry up through thedevice-forming step. After forming the absorbable surgical device, theinherent viscosity of the device should be ≧1.0, preferably ≧1.2.Inherent viscosity is measured at 30° C. at a concentration of 0.25 g ofpolymer/dl of solution in a suitable solvent, such as chloroform for thefirst-stage polymer or hexafluoroisopropanol for the two-phasecomposition, using a Ubbelohde viscometer.

After cooling, 1,362 grams of polymer (still in the vacuum oven) aretransferred to a dry room (temperature 20° C., relate humidity of lessthan 10%). A 4-quart conical/vertical reactor made by Atlantic ResearchCorporation (model 4CV) is dried by heating to 120° C. or more under anitrogen or argon flow and is placed in the dry room.

The vacuum in the oven is released by bleeding in argon. The copolymeris quickly loaded into the reactor while argon is flowing through thereactor. The reactor is sealed, pressurized to about 5 psi, andconnected to a temperature controller, hot oil circulator, and an argontank. The settings on the temperature controller and hot oil circulatorare maintained at about 180°-190° C. When the pot temperature reaches170° C., stirring is staged. As soon as a homogeneous melt is obtainedand pot temperature is 175°-180° C., 320 grams of purified glycolide areadded (430 grams of glycolide if the preferred composition with anoverall content of 35% m glycolide moieties is to be made).

When glycolide addition is completed, the reactor is resealed,repressurized, and the stirring rate is increased. When the pottemperature reaches 180° C., the stirring rate is reduced. If the pottemperature continues to rise, the oil bath temperature is reduced to175° C. 30-60 minutes after addition of the glycolide is complete, thetwo-phase polymer composition is removed from the reactor and is ground,dried, and ether extracted as described above.

The preferred scheme for making the two-continuous-phase polymericcomposition using the second scheme (no removal or purification of theintermediate polymer) is illustrated by the following two examples.

In the first example, purified L-lactide (1,362 grams, 9.4583 gmoles)with 0.02% by weight stannous octoate is placed in a clean and dryreactor (the same type of conical/vertical reactor as described above),which is then sealed and pressurized to about 5 psi with a dry, inertgas (argon or nitrogen). The lactide is polymerized for 14 hours at155°-160° C. The temperature is then raised to 175°-180° C. and 731.4grams (6.3056 gmoles) of purified glycolide are added. The mixture isvigorously stirred until the temperature rises to 180° C. and thenstirring is slowed to a low speed. The reaction mixture is held at180°-185° C. for 50-60 minutes, and then the two-phase polymer isremoved from the reactor, ground, and extracted as described above toremove residual monomer. The overall molar ratio of monomers used is40/60 glycolide/L-lactide. The glycolide content of the lactide-richphase is about 5% m and the overall glycolide content of the final,two-phase composition is about 40% m.

In a second example of the second scheme for making thetwo-continuous-phase composition, purified L-lactide (1,250.1 grams,8.6813 gmoles) and purified glycolide (111.9 grams, 0.9646 gmoles) with0.02% by weight stannous octoate are placed in a clean and dryconical/vertical retort, which is then sealed and pressurized to about 5psi with a dry, inert gas (argon or nitrogen). The mixture ispolymerized for 14 hour at 155°-160° C. The temperature is then raisedto 175°-180° C. and 430.4 grams of purified glycolide (3.7103 gmoles)are added. The mixture is vigorously stirred until the temperature risesto 180° C. and then stirring is slowed to a low speed. The reactionmixture is held at 180°-185° C. for 30-60 minutes and then the copolymeris removed from the reactor, ground, and extracted as described above toremove residual monomer. The overall molar ratio of monomers used is35/65 glycolide to L-lactide. The glycolide moiety content of thelactide-rich phase is about 10% m and the overall glycolide moietycontent of the final, two-phase composition is about 35% m.

In the preferred continuous/discrete two-phase composition, the discretephase is preferably 100% polyglycolic acid (i.e., 100% m derived fromglycolide moieties) of small particle size (generally less than 10microns). A preferred way of making those particles is as follows. Thisdiscussion assumes manufacture of a specific quantity of small particlesize polyglycolic acid. Other quantities may be made by modifying theprocedure.

1,500milliliters of toluene are placed in a 4-neck, 3-liter round bottomflask equipped with a heating mantle and a stirrer in the center neck.Two other stirrers are placed in two of the other necks to act asbaffles. A thermowell for a thermocouple is placed in the fourth neckfor temperature control.

The toluene is heated to 100° C. (with stirring). 500 to 520 grams ofpure glycolide are added and the solution temperature is brought back upto 100° C. 3 grams of stannous octoate in 10 cc of toluene are added viasyringe. The reaction mixture should be well stirred. A whiteprecipitate will form within a few minutes.

A well-mixed solution of 10 grams of stannous octoate, 10 grams oflauryl alcohol, and 80 cc of toluene is prepared and 10 cc of it areadded via syringe to the reaction mixture every 30 minutes. The heatingmantel is removed from the reaction flask after the last addition andthe reaction mixture is allowed to cool to approximately 50° C.

A fine white powder will be dispersed in the reaction mixture. Thepowder is recovered by filtration and extracted with boiling acetone for15 minutes. The powder is filtered and washed with ethyl ether. Theether is removed from the powder by vacuum filtration and the powder isdried in a vacuum oven at 100° C. and less than 10 mm Hg for about 10-15hours. The powder is comminuted in a ball mill with 7-10 ceramic ballsfor about 1 hour. The ground particles are screened to remove any largeagglomerates and are then blended with a lactide-rich polymer andinjection molded to form the surgical devices.

Two-continuous-phase compositions were made using the first scheme(intermediate polymer recovery and purification) and tested to show theadvantages of this invention. The results are reported in the followingtables. In those tables, the glycolide moiety contents of the two-phasepolymeric compositions are indicated by a four-digit code, for example"1030." The first two digits ("10") indicate the glycolide moietyconcentration in the monomer mixture used to make the lactide-rich phaseand the last two digits ("30") indicate the overall glycolide moietyconcentration in the monomer mixtures used to make the entire two-phasecomposition. For that example the glycolide moiety concentrations of thelactide-rich phase and overall are approximately 10% m nd 30% m,respectively.

Table I shows the tensile strengths of the hinge portion, thecrystallinities (as measured by x-ray diffraction), the approximatedistortion temperatures, and the times to failure in hot-wet creep testsof surgical clips having essentially the configuration shown in U.S.Pat. application Ser. No. 429,250, filed Sep. 30, 1982, made ofdifferent annealed and unannealed two-phase compositions and of two"control" compositions. Each control composition is a one-phase,substantially amorphous material made by the method disclosed in U.S.Pat. application Ser. No. 436,056, filed Oct. 22, 1982. Controlcomposition I contains approximately 20% m glycolide moieties and 80% mlactide moieties and control composition II contains approximately 30% mglycolide moieties and 70% m lactide moieties.

The tensile strengths were measured using an Instron tester at acrosshead speed of 0.02 inches per minute. The time to failure in thehot-wet creep test is the time required for the clip to fail, that is,allow air to pass through an externally clipped flexible tube, when thetube is subjected to an internal 2 psi pressure applied at one-hourintervals. Between pressurizations, the clip is immersed in water at103° F.

                                      TABLE I                                     __________________________________________________________________________                          Crystallinity (%)                                              Tensile Strength (psi)                                                                       L-Rich                                                                            G-Rich   Distortion                                                                          Hot-Wet Creep                        Material                                                                             At Peak Load                                                                         At Yield Load                                                                         Phase                                                                             Phase                                                                             Overall                                                                            Temp. (°F.)                                                                  Failure (hours)                      __________________________________________________________________________    Control I                                                                            7330 ± 670                                                                        5200 ± 800                                                                         --  --  5     125  3-5                                  Control II                                                                           --     --      --  --  --   <125  --                                   1030   6920 ± 850                                                                        5100 ± 300                                                                         0   1-2   1-2                                                                               130  4-6                                  (unannealed)                                                                  1030   9020 ± 380                                                                        5400 ± 600                                                                         7.5-15                                                                            3-6 10.5-21                                                                            >160  >72                                  (annealed)                                                                    1035   7640 ± 330                                                                        5600 ± 600                                                                         0   2.5-5                                                                             2.5-5                                                                               135  6-8                                  (unannealed)                                                                  1035   8760 ± 310                                                                         6600 ± 1300                                                                       10-20                                                                             3-6   13-26                                                                            >160  >72                                  (annealed)                                                                    __________________________________________________________________________

The results show that annealing significantly increases the tensilestrength of surgical devices made from the new two-phase composition.The results also show that annealing has little effect on thecrystallinity of the glycolide-rich phase but a significant effect onthe crystallinity of the lactide-rich phase. The results also show thatannealed surgical devices made of the new multi-phase composition havesignificantly higher distortion temperatures than devices made of asubstantially amorphous composition having the same overall composition(compare Control II with "1030 annealed"). The results also show thesuperior hot-wet creep resistance of the annealed devices of thisinvention.

The following table shows how annealing affects the rate of loss of peaktensile strength of surgical staples made using the compositions of thisinvention and made using the control compositions. The stapleconfiguration is substantially the same as that shown in U.S. Pat.application No. 480,423, filed Mar. 30, 1983, which application ishereby incorporated by reference. For the in vitro tests, the stapleswere placed in a buffer solution (pH=7.0) at 37° C. After 7 and 14 days,several staples were withdrawn and tested using an Instron tester(crosshead speed of 0.02 inches/minute). For the in vivo tests, stapleswere implanted in abdominal and muscular tissues in rats (two staplesper rat). After 14 and 21 days each, five rats were specified and thestaples were removed and tested using an Instron tester (crosshead speedof 0.02 inches/minute). The in vivo tensile strengths shown below areavperages of the abdominal and muscular values.

                  TABLE II                                                        ______________________________________                                        Percentage Of Initial Tensile Strength Remaining                                         In Water   In Rats                                                 Material Initial 7 days  14 days                                                                              14 days                                                                              21 days                                ______________________________________                                        Control I                                                                              100     100     100    >100   >100                                   Control II                                                                             100     --      --     52     27                                     0040     100     63      49     37     40                                     (unannealed)                                                                  0040     100     --      --     --     --                                     (annealed)                                                                    1030     100     99      86     --     --                                     (unannealed)                                                                  1030     100     73      43     --     --                                     (annealed)                                                                    1035     100     92      81     --     --                                     (unannealed)                                                                  1035     100     49      33     33     10                                     (annealed)                                                                    ______________________________________                                    

The results show that annealing significantly increases the in vitrorate of loss of tensile strength. Other tests have shown that for thecompositions of this invention, rate of loss of tensile strength invitro is an excellent predictor of and closely matches the rate of lossof tensile strength in vivo.

Many modifications and variations in the new invention may be made. Forexample, the new composition has been described as being two-phase. Itis possible that three or more stages of monomer additionalpolymerization could be used. The resulting multi-phase polymer wouldthen have more than two phases. However, it still should have alactide-rich first phase constituting at least 50% by weight of thetotal composition and have no more than about 25% m glycolide moieties.The two or more other phases would then have lactide and glycolidemoieties in amounts such that the overall multi-phase composition and nomore than about 45% m glycolide moieties.

Another possible variation when preparing an interpolymer composition ofthis invention (all phases continuous) is to use the crude multi-phasepolymeric composition from the final polymerization stage (without anypurification) for making the surgical devices.

Another possible variation is to interpolymerize several continuousphases, but also add one or more discrete phases.

Other modifications and variations will be apparent to those skilled inthe art and the claims are intended to cover all such modifications andvariations that fall within the true spirit and scope of the invention.

We claim:
 1. A process of molding an absorbable surgical articlecomprising the steps of:providing a dry two-phase polymer compositioncomprising a glycolide-rich polymer dispersed in a matrix of alactide-rich polymer, the overall composition having a predominantamount of lactide moieties; placing the composition in a first hopper;applying a vacuum to and slowly heating the composition within the firsthopper to maintain the composition in a dry condition; thereafterpassing the dried two phase polymeric composition into a second hopperafter the composition has been heated in the first hopper; feeding thedried two phase polymeric composition from the second hopper to aninjection molding apparatus; and injecting the composition into a moldand recovering the molded article.
 2. The process of claim 1 wherein thepressure in said first hopper is no higher than about 5 m Hg.
 3. Theprocess of claim 1 wherein he pressure in said first hopper is no higherthan about 0.1 mm Hg.
 4. The process of claim 1 wherein the compositionis maintained in said first hopper for about 15 hours.
 5. The processaccording of claim 1 wherein the composition is maintained in said firsthopper at an elevated temperature under vacuum for at least about onehour.
 6. The process of claim 5 wherein the elevated temperature is 50°to 70° C.
 7. The process of claim 5 wherein the injection molding iscarried out at a temperature less than the melting point of the polymerof the glycolide rich phase.
 8. The process of claim 5 wherein saidfirst hopper, said second hopper and said injection molding apparatusare padded or purged with a dry inert gas.
 9. The process according toclaim 1 wherein the second hopper is under vacuum.
 10. The process ofclaim 1 wherein the first hopper is heated to 50° to 70 ° C.
 11. Theprocess of claim 1, wherein the second hopper is preheated.
 12. Theprocess of claim 1, wherein the second hopper is not under vacuum.